Electrolytic synthesis method of pyrazolone compound intermediate

Abstract

The invention discloses an electrolytic synthesis method of a pyrazolone compound intermediate, which comprises the following steps: by taking a nitroso acid ester compound as a raw material, carrying out electrochemical reduction to obtain an electrolyte containing a hydrazine compound; and carrying out cyclization reaction on the electrolyte containing the hydrazine compound to obtain the pyrazolone compound. According to the method, a diazotization reaction with high risk is replaced by a mild and efficient electrochemical reduction mode, and the pyrazolone compound is synthesized; the electrolyte can be recycled for multiple times, so that a large amount of reagents such as sulfite and acid are prevented from being added in the synthesis process, and the generation of a large amount of three wastes is reduced. The method provided by the invention has better product purity (gt; 95%) and yield (gt; and the method is more environment-friendly, does not generate three wastes, and is suitable for industrial production.

Description

(I) Technical field

[0001] The invention relates to an electrolytic synthesis method for a pyrazolone compound intermediate, in particular to an electrochemical reduction synthesis method. (II) Background technology

[0002] Pyrazolone compounds are an important organic fine chemical raw material and pharmaceutical synthesis intermediate, widely used in the production of medicines, dyes, color film dyes, pesticides and organic synthesis. In the field of medicine, they have anti-inflammatory, antibacterial, antiviral and anti-tumor biological activities, and are often used as drug skeletons or groups to improve drug efficacy. In the field of pesticides, pesticides containing this structural skeleton have become popular varieties due to their high efficiency, low toxicity, broad spectrum, safety and friendliness. Among them, pyraclostrobin is ranked among the top ten varieties in the world and is widely used.

[0003] However, there are many problems with the traditional synthesis method of pyrazolone compounds. At present, the most common synthesis method is to use hydrazine or hydrazine substituents and ketone compounds as raw materials, and then treat them with hydrazine hydrate catalyst to obtain pyrazolone. Hydrazine hydrate catalyst is often produced by reaction under high temperature and high pressure with urea, sodium hypochlorite and sodium hydroxide as raw materials in industry. During the reaction process, urea is hydrolyzed under alkaline conditions to generate ammonia and carbon dioxide, ammonia reacts with sodium hypochlorite to generate chloramine, and chloramine reacts with excess ammonia to generate hydrazine hydrate. The reaction conditions are relatively harsh, and the method has serious environmental pollution and potential safety hazards. Other methods such as hydrogen peroxide oxidation method and ketone azine method also have their own shortcomings. Among them, hydrogen peroxide oxidation method has potential safety hazards and is not yet mature in China; the acetone added in the ketone azine method affects the purity of the product and increases the post-processing cost of acetone vapor. In addition, if the substituent in the substituted hydrazine is an aromatic substituent, the synthesis of its raw materials needs to go through diazotization and sodium sulfite steps, which has high safety risks and a large amount of three wastes, which is not conducive to industrial production.

[0004] Organic electrosynthesis is a branch of organic synthesis. Compared with general organic synthesis, the organic electrosynthesis process occurs on two electrodes for oxidation and reduction reactions, and the exchange of substances and electrons occurs at the electrode solution interface. Generally, no oxidation or reduction reagents are required, and it can be carried out at room temperature and pressure. The reaction is controlled by adjusting parameters such as potential and current density, which is convenient for automatic control. In essence, organic electrosynthesis reactions use clean "electronic" reagents and electrodes as electron acceptors, which reduces the generation of chemical waste and improves production safety, fully meeting the requirements of "atom economy". With high product yield, few side reactions, and less pollution from three wastes, organic electrosynthesis eliminates the root causes of environmental pollution caused by traditional organic synthesis as much as possible, meets the requirements of green chemistry, and is therefore called a high-tech technology for producing "green products" in the 21st century.

[0005] Therefore, it is necessary to find a green and efficient synthesis method for hydrazine compounds, which are intermediates of pyrazolone compounds. (III) Summary of the invention

[0006] The present invention aims to provide an electrolytic synthesis method for a pyrazolone compound intermediate, which overcomes the problems of high safety risk, large amount of three wastes and disadvantages for industrial production in the prior art.

[0007] The technical solution adopted by the present invention is:

[0008] The invention provides an electrolytic synthesis method for a pyrazolone compound intermediate. The method uses a nitrosoester compound as a raw material and obtains an electrolyte containing a hydrazine compound (pyrazolone compound intermediate) by electrochemical reduction; the electrolyte can be directly used for the pyrazolone compound.

[0009] Furthermore, the electrochemical reduction uses a solution containing a nitrosoester compound, an electrolyte and / or a reducing medium as an electrolyte; the reducing medium is used for indirect electroreduction and includes anthracene, phenanthrene, zinc salt, tetramethylpiperidinoxide (TEMPO), ferrocene, 9-azabicyclo[3.3.1]nonane-N-oxide (ABNO), N-hydroxyphthalimide (NHPI), preferably ZnCl2.

[0010] Furthermore, the solvent of the electrolyte is water or an organic solvent, and the organic solvent includes one or more of alcohols, ketones, ethers, nitriles, esters, and halogenated hydrocarbons, preferably methanol, acetonitrile (ACN), ethyl acetate, 1,4-dioxane, and methyl isobutyl ketone (MIBK); the electrolyte includes quaternary ammonium salts (PhSO3Na, NaHBF4, TEABF4), metal hydroxides, chlorides (NH4Cl, KCl, IBr), and carbonates, preferably tetraethylammonium tetrafluoroborate (TEABF4) among quaternary ammonium salts.

[0011] Furthermore, the concentration of nitrosoester compounds in the electrolyte is 0.05-1.2 mol / L (preferably 0.3 mol / L), the electrolyte concentration is 0.1-2 mol / L (preferably 0.5 mol / L); the reducing medium concentration is 0-1.5 mol / L (preferably 0.5 mol / L, and no reducing medium needs to be added when direct electroreduction is used), and the solvent is methanol.

[0012] Furthermore, the electrochemical reduction reaction uses a metal electrode, a graphite electrode, or a metal oxide coated material or a composite electrode as the cathode; the metal electrode includes mercury, silver, tin, iron, zinc, copper, titanium, nickel, lead, and platinum; the material containing a precious metal oxide coating includes titanium containing a ruthenium oxide coating), and the preferred cathode material is titanium; the electrode shape can be a plate, rod, wire, mesh, mesh, wool, sheet, arc or porous, preferably a screen.

[0013] Furthermore, the anode reaction is a hydrogen evolution reaction, a sacrificial anode reaction, a sacrificial ammonium salt reaction, or a hydrogen oxidation reaction, and preferably a chemically inert material is used as the anode.

[0014] Furthermore, the chemically inert material includes platinum, iridium graphite, carbon, nickel-based alloy (such as Hastelloy C) or a material containing a metal oxide coating (such as a silver material containing silver oxide), preferably platinum.

[0015] Furthermore, the electrochemical reduction is carried out in a diaphragm electrolyzer or a diaphragmless electrolyzer. The diaphragm of the diaphragm electrolyzer includes an ion membrane Nafion 417, and a sulfuric acid aqueous solution is used as the anolyte, preferably a 2 mol / L sulfuric acid aqueous solution.

[0016] Furthermore, the electrochemical reduction reaction temperature is -40°C to 75°C.

[0017] Furthermore, the cathode potential of the electrochemical reduction is -0.2 to -2.5 V relative to the Ag / Ag+ reference electrode, and the preferred electrode potential is -1.95 V.

[0018] Furthermore, the structure of the nitrosoester compound is shown in Formula II, and the structure of the hydrazine compound is shown in Formula III:

[0019]

[0020] In Formula II, X1 and X2 each independently represent H, C 1- C6 alkyl, C 1- C6 substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, polycyclic, substituted polycyclic, heterocyclic, substituted heterocyclic, carboxyl, ester, halogen, amide, substituted amide; the substituted groups include aryl, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, carboxyl, ester, halogen, deuterium, cyano;

[0021] Y independently represents H, C 1- C6 alkyl, C 1-C6 substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, polycyclic, substituted polycyclic, heterocyclic, substituted heterocyclic, amide, nitroso, amino, keto, carboxyl, ester; the substitution groups include alkyl, cycloalkyl, halogen, aryl, carboxyl, ester, hydrogen deuterium, cyano;

[0022] R represents C1-C6 alkyl, C1-C6 substituted alkyl, amino, substituted amino, aryl, substituted aryl, keto, acyl, hydroxyl; the substituents include alkyl, halogen, aryl, carboxyl, cyano;

[0023] In formula III, X1, X2, Y and R are the same as those in formula II.

[0024] Furthermore, in formula II, X1 is preferably hydrogen or methyl; X2 is preferably hydrogen, methyl or carboxyl; Y is preferably methyl, deuterated methyl (CD3), nitroso, propylcarboxyl, phenyl, p-chlorophenyl, aromatic heteroyl, o-methoxyphenyl or benzoylamide; R is preferably methyl, hydroxyl, ethoxy, methoxy, amino, phenyl or p-benzyloxy; X2 and Y form indoline or piperidine; X1 and X2 form a benzene ring or aromatic cyanide.

[0025] The electrolyte containing the hydrazine compound of formula III of the present invention directly undergoes a cyclization reaction to prepare the pyrazolone compound of formula I. The cyclization reaction method is that the electrolyte containing the hydrazine compound is heated to 65-85° C. and after the cyclization reaction is complete, the reaction solution is separated and purified to obtain the pyrazolone compound.

[0026] Furthermore, the method is as follows: after the electrolyte containing the hydrazine compound shown in formula III is heated to 65-85°C and the cyclization reaction is complete, the reaction solution is cooled to room temperature, concentrated by rotary evaporation until no liquid flows out to remove the solvent, the obtained concentrated solution is added with diethylene glycol dimethyl ether to dissolve, and then filtered to remove the filter cake containing the electrolyte and zinc salt, the filtrate is rotary evaporated until no liquid flows out, and then vacuum dried at 60°C to obtain the pyrazolone compound shown in formula I.

[0027]

[0028] In formula Ⅰ, X1, X2, and Y are the same as those in formula Ⅱ.

[0029] The reactions involved in the electrolytic synthesis method of pyrazolone compounds of the present invention are:

[0030] Cathode reaction:

[0031]

[0032] Anode reaction:

[0033] 2H2O-4e - →O2↑+4H +

[0034] Cyclization reaction:

[0035]

[0036] Those skilled in the art will appreciate that the reduction order of functional groups is not fixed, but is determined by the reaction conditions and the activity of the functional groups. Therefore, in practical applications, the reaction system and conditions need to be determined according to the specific type of functional group to be reduced.

[0037] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0038] (1) The present invention adopts an electrochemical reduction method to synthesize hydrazine compounds using nitrosoester compounds as raw materials. The reaction conditions are mild, the yield of hydrazine compounds is as high as more than 80%, and the risk of diazotization reaction is reduced.

[0039] (2) The electrolyte of the present invention can be directly used for the synthesis of pyrazolone compounds by cyclization reaction, and the electrolyte can be recycled for multiple times, thereby avoiding the need to add a large amount of reagents such as sulfite and acid during the synthesis process, and reducing the generation of a large amount of "three wastes".

[0040] (3) The method of the present invention has better purity (>95%) and yield (>80%) of pyrazolone compounds, and the method is more environmentally friendly, does not generate three wastes, and is suitable for industrial production. (IV) Description of the drawings

[0041] Figure 1 , NMR spectrum of the cathode liquid after the electrolysis of Example 6.

[0042] Figure 2 , NMR spectrum of the cathode liquid after cyclization reaction of Example 6. (V) Specific implementation methods

[0043] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0044] Example 1: Preparation of pyrazolone compounds by indirect electroreduction method

[0045] (1) Electroreduction reaction

[0046] A diaphragm electrolyzer was used, with Nafion 417 as the ion membrane and an area of ​​1 cm 2 The platinum sheet is the anode, with an area of ​​8.75cm 2The titanium mesh was used as the cathode. A 2 mol / L sulfuric acid aqueous solution was used as the anode solution (40 mL), a methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate, 0.3 mol / L raw material II-1 in Table 1, and 0.5 mol / L ZnCl2 was used as the cathode solution (40 mL), and an Ag / AgNO3 reference electrode was inserted into the cathode solution. The reaction temperature was 0°C, and a current of 300 mA (cathode current density was 3.4 A / dm 2 , anode current density: 20.8A / dm 2 , reduction potential is -1.5V vs Ag / Ag + ), the cathode liquid was sampled and HPLC was used to detect the raw material concentration. The electrolysis reaction was completed after 3 hours, and the cathode liquid containing intermediate III-1 was obtained, and the intermediate yield was 97.8%.

[0047] (2) Cyclization reaction

[0048] The cathode liquid of step (1) was divided into three parts, and the temperatures were respectively raised to 65, 75, and 85° C. for cyclization reaction for 10 hours. After the reaction was completed by TLC, the reaction solution was cooled to room temperature and concentrated by rotary evaporation until no liquid flowed out to remove the solvent. The obtained concentrated solution was added with 20 mL of diethylene glycol dimethyl ether for dissolution and then filtered to remove the filter cake containing electrolyte and zinc salt. The filtrate was rotary evaporated until no liquid flowed out and then vacuum dried at 60° C. to obtain 0.906 g, 0.983 g, and 0.945 g of product I-1, respectively. The mass yields were 87.7%, 95.1%, and 91.5%, respectively. The purities detected by HPLC were 95.3%, 98.8%, and 96.5%, respectively.

[0049] HPLC detection conditions: Acclaim C18 (4.5 μm*250 nm), T=25° C., λ=254 nm, elution method: 0 min: v=0.8 ml / min, water:acetonitrile=50%; 20 min: v=1.0 ml / min, water:acetonitrile=30%.

[0050] The developing solvent for TLC detection was: ethyl acetate / n-hexane = 1:3.

[0051] Example 2-17: Preparation of pyrazolone compounds by indirect electroreduction method

[0052] The raw material II in Example 1 was replaced according to Table 1, the cyclization temperature was 75°C, and the other operations were the same as in Example 1. The detection was carried out using the method of Example 1. The results are shown in Table 1.

[0053] Table 1 Yield and purity of pyrazolone compounds

[0054]

[0055]

[0056] Example 18: Preparation of 1-(4-chlorophenyl)-3-pyrazolone (I-6) by direct electroreduction method

[0057] (1) Electroreduction reaction

[0058] A diaphragm electrolyzer was used, with Nafion 417 as the ion membrane and an area of ​​1 cm 2 The platinum sheet is the anode, with an area of ​​8.75cm 2 The copper foam was used as the cathode. A 2 mol / L sulfuric acid aqueous solution was used as the anode liquid (40 mL), and a methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate and 0.3 mol / L raw material II-6 was used as the cathode liquid (40 mL). The reaction temperature was 0°C, and a current of 300 mA was applied (cathode current density was 3.4 A / dm 2 , anode current density: 20.8A / dm 2 , the reduction potential is -1.1V vs Ag / Ag + ), the cathode liquid was sampled and HPLC was used to detect the raw material concentration. The electrolysis reaction was completed after 3 hours, and the cathode liquid containing intermediate III-6 was obtained with a yield of 52.2%.

[0059] (2) Cyclization reaction

[0060] The cathode liquid was heated to 75° C. for cyclization reaction for 10 hours. Other operations were the same as in Example 1 to obtain product I-6 with a yield of 47.0% and a purity of 87.5%.

[0061] Example 19: Electropreparation of 1-(4-chlorophenyl)-3-pyrazolone by sacrificial anode method

[0062] (1) Electroreduction reaction

[0063] The electrolytic cell is 8.75 cm2 without diaphragm. 2 The zinc sheet is the anode, with an area of ​​8.75cm 2 The titanium mesh was used as the cathode. A methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate and 0.3 mol / L raw material (no additional ZnCl2) Ⅱ-6 was used as the cathode solution (40 mL). The reaction temperature was 0°C and a current of 300 mA was applied (cathode current density was 3.4 A / dm 2 , anode current density: 3.4A / dm 2 , the reduction potential is -0.89V vs Ag / Ag + ), the cathode liquid was sampled and HPLC was used to detect the raw material concentration. The electrolysis reaction was completed after 3 hours, and the cathode liquid containing intermediate III-6 was obtained with a yield of 95.9%.

[0064] (2) Cyclization reaction

[0065] The cathode liquid was heated to 75°C for cyclization reaction for 10 hours. Other operations were the same as in Example 1 to obtain product I-6 with a yield of 87.3% and a purity of 95.3%.

[0066] Example 20: Electropreparation of 1-(4-chlorophenyl)-3-pyrazolone by sacrificial ammonium salt method

[0067] (1) Electroreduction reaction

[0068] A diaphragm electrolyzer was used with Nafion 417 as the ion membrane and an area of ​​17.5 cm 2 The graphite plate is the anode, with an area of ​​8.75cm 2 The titanium mesh was used as the cathode. A methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate, 0.3 mol / L raw material II-6, and 0.5 mol / L ZnCl2 was used as the cathode solution (40 mL), and an ammonia solution containing 0.01 mol / L ammonium chloride was used as the anode solution. The reaction temperature was 0°C, and a current of 300 mA was applied (the cathode current density was 3.4 A / dm 2 , anode current density: 1.7A / dm 2 , the reduction potential is -0.98V vs Ag / Ag + ), the cathode liquid was sampled and the raw material concentration was detected by HPLC, 0.1 ml of 98% hydrochloric acid was added to the cathode liquid every half an hour of electrolysis, and the reaction was completed after 3 hours of electrolysis to obtain a cathode liquid containing intermediate III-6 with a yield of 94.7%.

[0069] (2) Cyclization reaction

[0070] The cathode liquid was heated to 75°C for cyclization reaction for 10 hours. Other operations were the same as in Example 1 to obtain product I-6 with a yield of 84.3% and a purity of 90.7%.

[0071] Example 21: Electropreparation of 1-(4-chlorophenyl)-3-pyrazolone by hydrogen oxidation reaction

[0072] (1) Electroreduction reaction

[0073] The electrolytic cell is 6.25 cm2 without diaphragm. 2 The platinum-plated gas diffusion electrode is used as the anode. The area is 8.75 cm 2 The titanium mesh was used as the cathode, and a methanol solution containing 0.5 mol / L tetraethylammonium tetrafluoroborate, 0.3 mol / L raw material II-6, and 0.5 mol / L ZnCl2 was used as the cathode liquid (40 mL). Hydrogen was introduced at a flow rate of 20 ml / min. The reaction temperature was 0°C, and a current of 300 mA was applied (the cathode current density was 3.4 A / dm 2 , anode current density: 4.8A / dm 2, the reduction potential is -0.88V vs Ag / Ag + ), the cathode liquid was sampled and HPLC was used to detect the raw material concentration. The electrolysis reaction was completed after 3 hours, and the cathode liquid containing intermediate III-6 was obtained with a yield of 68.6%.

[0074] (2) Cyclization reaction

[0075] The cathode liquid was heated to 75°C for cyclization reaction for 10 hours. Other operations were the same as in Example 1 to obtain product I-6 with a yield of 62.1% and a purity of 89.3%.

[0076] Example 22-51: Optimization of conditions for the synthesis of 1-(4-chlorophenyl)-3-pyrazolone by indirect electroreduction method

[0077] According to Table 2, raw material II-6 was used as raw material, and the electro-reduction reaction was carried out by the method of step (1) of Example 1. The influencing factors such as cathode material, cathode liquid composition, current density, temperature, reduction potential, etc. were investigated. The results are shown in Table 2: the yield of intermediate III-6 is less affected by temperature, current density, cathode material, and reducing medium concentration. The type of electrolyte has a certain influence on the yield. The reaction is preferably carried out at -40-40°C.

[0078] Table 2 Effect of different conditions on electrolysis reaction a

[0079]

[0080]

[0081]

[0082] Remark: a Other unspecified conditions are consistent with those in Example 1; S indicates that the conditions are consistent with those in Example 1.

Claims

1. A method for electrolytic synthesis of a pyrazolone compound intermediate, characterized in that: The method uses nitroso acid ester compounds as raw materials and obtains an electrolyte containing hydrazine compounds through electrochemical reduction.

2. The method according to claim 1, characterized in that The electrochemical reduction uses a solution containing nitroso acid ester compounds, electrolytes and / or reducing media as an electrolyte; the reducing media includes anthracene, phenanthrene, zinc salt, tetramethyl piperidine oxide, ferrocene, 9-azabicyclo[3.3.1]nonane-N-oxide, and N-hydroxyphthalimide.

3. The method according to claim 2, characterized in that The solvent of the electrolyte is water or an organic solvent, and the organic solvent includes one or more of alcohols, ketones, ethers, nitriles, esters, and halogenated hydrocarbons; the electrolyte includes quaternary ammonium salts, metal hydroxides, chlorides, iodides, bromides, benzenesulfonates, fluoroborates, and carbonates.

4. The method according to claim 2, characterized in that The concentration of the nitrosoester compound in the electrolyte is 0.05-1.2 mol / L, the concentration of the electrolyte is 0.1-2 mol / L, and the concentration of the reducing medium is 0-1.5 mol / L.

5. The method according to claim 1, characterized in that The anode reaction of the electrochemical reduction is a sacrificial anode reaction, a sacrificial ammonium salt reaction, a hydrogen oxidation reaction, and a hydrogen evolution reaction.

6. The method according to claim 1, characterized in that The cathode electrode for electrochemical reduction includes a metal electrode, a graphite electrode, or a material containing a precious metal oxide coating, or a composite electrode; the material containing a metal oxide coating includes titanium containing a ruthenium oxide coating; the metal electrode includes mercury, silver, tin, iron, zinc, copper, titanium, nickel, lead, and platinum.

7. The method according to claim 1, characterized in that The temperature of electrochemical reduction is -40°C to 75°C.

8. The method according to claim 1, characterized in that The cathode potential of the electrochemical reduction is -0.2 to -2.5 volts relative to the Ag / Ag+ reference electrode.

9. The method according to claim 1, characterized in that The structure of the nitrosoester compound is shown in Formula II, and the structure of the hydrazine compound is shown in Formula III: In Formula II, X1 and X2 each independently represent H, C 1- C6 alkyl, C 1- C6 substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, polycyclic, substituted polycyclic, heterocyclic, substituted heterocyclic, carboxyl, ester, halogen, amide, substituted amide; the substituted groups include aryl, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, carboxyl, ester, halogen, deuterium, cyano; Y independently represents H, C 1- C6 alkyl, C 1- C6 substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, polycyclic, substituted polycyclic, heterocyclic, substituted heterocyclic, amide, nitroso, amino, keto, carboxyl, ester; the substitution groups include alkyl, cycloalkyl, halogen, aryl, carboxyl, ester, hydrogen deuterium, cyano; R represents C1-C6 alkyl, C1-C6 substituted alkyl, amino, substituted amino, aryl, substituted aryl, keto, acyl, hydroxyl; the substituents include alkyl, halogen, aryl, carboxyl, cyano; In formula III, X1, X2, Y, and R are the same as those in formula II; in formula I, X1, X2, and Y are the same as those in formula II.

10. The method according to claim 1, characterized in that After the electrolyte containing the hydrazine compound is heated to 65-85° C. and the cyclization reaction is complete, the reaction solution is separated and purified to obtain the pyrazolone compound.

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